JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2023
·
IF 5.3
Li Liu,Rong Zhang,Chang Chen,Changbo Xia,Guangda Yao,Xiaogang He,Baomei Xia
It has been reported that Banxia-houpo decoction (BXHPD) serves as the anti-depressant treatment for a mild and severe depressive disease with limited side effects. The present study was performed to evaluate the protective effect of BXHPD on chronic unpredicted mild stress (CUMS)-induced depression and explore its effect on TrkA/Akt-mediated microglia polarization. The CUMS procedure was carried out, and the mice were intragastrically treated with BXHPD once daily. The selective TrkA inhibitor GW441756 was applied to further investigate the role of TrkA in BXHPD-mediated microglia polarization. The behaviour test including open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), tail suspension test (TST) and forced swim test (FST) was performed. The concentrations of pro-inflammatory cytokines IL-6, TNF-α, IL-1β, IL-12 and anti-inflammatory cytokines IL-4, IL-10 were determined using Enzyme-linked immunosorbent assay. The population of Iba1+ cells and the length of microglia processes were observed under the fluorescence microscope. The mRNA expressions of Arg1, Ym1 and Fizzl1 were measured by PCR. The protein expressions of TrkA, p-Tyr490-TrkA, p-Ser473-Akt, p-Ser473-Akt1, p-Ser474-Akt2, p-CREB and Jmjd3 were detected by western blot. Our results showed that BXHPD attenuated CUMS-induced depressive-like behaviour, promoted anti-inflammatory cytokines, inhibited pro-inflammatory cytokines, suppressed microglia activation, promoted M2 phenotype-specific indices and upregulated the expressions of TrkA, p-Tyr490-TrkA, p-Ser473-Akt, p-Ser473-Akt1, p-Ser474-Akt2, p-CREB and Jmjd3. The above beneficial effect of BXHPD can be blocked by TrkA inhibitor GW441756. This work demonstrated that BXHPD exerted an anti-depressant effect by promoting M2 phenotype microglia polarization via TrkA/Akt pathway.
研究领域:
药理学
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神经科学
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精神病学
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DOI
PubMed
高影响因子
iScience
·
2022
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IF 6.107
Tianyou Yang,Jiahao Li,Zhenjian Zhuo,Huijuan Zeng,Tianbao Tan,Lei Miao,Manna Zheng,Jiliang Yang,Jing Pan,Chao Hu,Yan Zou,Jing He,Huimin Xia
Summary Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children. We found that TTF1, TrkA, and miR-204 were lowly expressed, whereas TrkB was highly expressed in undifferentiated NB tissues. Meanwhile, TTF1 expression correlated positively with TrkA and miR-204 expression but negatively with TrkB expression. The TTF1 promoter was hypermethylated in undifferentiated NB tissues and SK-N-BE cells, leading to TTF1 downregulation. We also identified miR-204, which directly targets TrkB, as a transcriptional target of TTF1. Functionally, TTF1 suppressed proliferation, migration, and invasion of NB cells, whereas induced cell cycle arrest, apoptosis, and autophagy of NB cells by regulating TrkA and the miR-204-TrkB axis. Furthermore, TTF1 suppressed tumor growth and promoted neurogenic differentiation in a NB xenograft mouse model. Our study demonstrates that TTF1 reduces tumor growth and induces neurogenic differentiation in NB by directly targeting TrkA and the miR-204/TrkB axis.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2022
·Vol. 44
·期 6
·1262-1276
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IF 7.169
Song Qi-qi,Lin Li-ping,Chen Ya-li,Qian Jia-cheng,Wei Ke,Su Jian-wei,Ding Jian-hua,Lu Ming,Liu Yang,Tan Ren-xiang,Hu Gang
Malignant glioma is the most fatal, invasive brain cancer with limited treatment options. Our previous studies show that 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1), a major metabolite of indole-3-carbinol (I3C) derived from cruciferous vegetables, produces anti-tumour effect against various tumour cell lines. In this study we characterized LTr1 as a novel anti-glioma agent. Based on screening 134 natural compounds and comparing the candidates’ efficacy and toxicity, LTr1 was selected as the lead compound. We showed that LTr1 potently inhibited the viability of human glioma cell lines (SHG-44, U87, and U251) with IC 50 values of 1.97, 1.84, and 2.03 μM, respectively. Furthermore, administration of LTr1 (100,300 mg· kg −1 ·d −1 , i.g. for 18 days) dose-dependently suppressed the tumour growth in a U87 xenograft nude mouse model. We demonstrated that LTr1 directly bound with TrkA to inhibit its kinase activity and the downstream PI3K/AKT pathway thus inducing significant S-phase cell cycle arrest and apoptosis in SHG-44 and U87 cells by activating the mitochondrial pathway and inducing the production of reactive oxygen species (ROS). Importantly, LTr1 could cross the blood-brain barrier to achieve the therapeutic concentration in the brain. Taken together, LTr1 is a safe and promising therapeutic agent against glioma through inhibiting TrkA/PI3K/AKT pathway.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Yizhong Peng,Xuanzuo Chen,Zilong Rao,Wei Wu,Huiyin Zuo,Kaibin Chen,Kanglu Li,Hui Lin,Sheng Liu,Yan Xiao,BaiChuan Wang,Daping Quan,Xiangcheng Qing,Ying Bai,Zengwu Shao
Chronic low back pain mainly attributed to intervertebral disc (IVD) degeneration. Endogenous damage-associated molecular patterns (DAMPs) in the injured IVD, particularly mitochondria-derived nucleic acid molecules (CpG DNA), play a primary role in the inflammatory responses in macrophages. M1-type macrophages form a chronic inflammatory microenvironment by releasing pro-inflammatory factors and nerve growth factor (NGF) that induce nerve growth into the inner annulus fibrosus, resulting in persistent hyperalgesia. We fabricated an amphiphilic polycarbonate that naturally forms cationic nanoparticles (cNP) in aqueous solutions, with the hydrophobic core loaded with TrkA-IN-1, an antagonist against the NGF receptor (TrkA). The drug delivery nanoparticles were denoted as TI-cNP. TrkA-IN-1 and TI-cNP were added to the decellularized annulus fibrosus matrix (DAF) hydrogel to form hybrid hydrogels, denoted as TI-DAF and TI-cNP-DAF, respectively. As a result, TrkA-IN-1 showed a delayed release profile both in TI-DAF and TI-cNP-DAF. Each mole of cNP could bind approximately 3 mol of CpG DNA to inhibit inflammation. cNP-DAF and TI-cNP-DAF significantly inhibited the M1 phenotype induced by CpG DNA. TI-DAF and TI-cNP-DAF reduced neurite branching and axon length, and inhibited the expression of neurogenic mediators (CGRP and substance P) in the presence of NGF. Besides, TI-cNP-DAF relieved mechanical hyperalgesia, reduced CGRP and substance P expression in the dorsal root ganglion, and downregulated GFAP and c-FOS signaling in the spinal cord in the rat disc herniation model. Summarily, TI-cNP-DAF, a novel composite IVD hydrogel, efficiently mediated the inflammatory environment, inhibited nerve ingrowth and sensitization, and could be clinically applied for treating discogenic pain. Statement of Significance : Discogenic lower back pain, related to intervertebral disc degeneration (IDD), imposes a tremendous health and economic burden globally. M1-type macrophages release pro-inflammatory factors and nerve growth factor (NGF) that induce nerve growth into the inner annulus fibrosus, resulting in persistent hyperalgesia and discogenic pain. Reconstructing matrix integrity and modulating the inflammatory microenvironment are promising strategies for preventing the ingrowth and activation of neurites. The TI-cNP-DAF hydrogel recovers tissue integrity, alleviates inflammation, and delivers the TrkA antagonist to inhibit the activity of NGF, thus restraining hyperinnervation and nociceptive input. Due to its simple production process, injectability, and acellular strategy, the hydrogel is operable and holds great potential for treating discogenic lower back pain.
研究领域:
生物医学工程
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神经科学
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疼痛管理
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组织工程
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2024
·
IF 2.8
Hongbei Liu,Qiumin Xu,Michael Adu-Frimpong,Yuchu Chen,Ran Li,Fei Xu,Xia Cao,Shanshan Tong
In order to enrich the selection of biological ligands, realize the miniaturization analysis, and broaden the application of monolith materials for active ingredients screening and separating, we sough to construct a lipid raft @capillary monolith microcolumn affinity chromatography model. Single factor experiments and various characterization methods, including scanning electron microscopy (SEM) and thermogravimetric analysis, were employed to investigate the polymerization of the monolith column under different material ratios to determine optimal preparation conditions. Subsequently, the lipid raft from U251 cells was integrated with the monolith materials based on epoxy-based covalent crosslinking principle and characterized through SEM and immunofluorescence methods. Afterwards, the retention of positive drug gefitinib, negative drug gemcitabine and four licorice standards solution on the prepared lipid raft monolith microcolumn was then detected via electrochemical detection. The results exhibited that there was no specific adsorption for any active compounds on the blank monolith materials. Significantly, the lipid raft monolith microcolumn packed with TrkA-target proteins could be successfully validated for positive drug gefitinib with a high affinity sorption efficiency of 51.2%. This work expands the range of the utilization of affinity chromatography carriers and the selection of biological ligands, providing a new idea for the screening of active ingredients.
研究领域:
分析化学
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药理学
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生物技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2023
·
IF 4.1
Hao Chi,Sheng Tian,Xiu Li,Yuchu Chen,Qiumin Xu,Qixiao Wang,Wenwan Shi,Michael Adu-Frimpong,Shanshan Tong
In order to improve the separation process of affinity chromatography that has silica as the main carrier material, we sought to construct Lipid [email protected] 4B affinity chromatography model. We extracted the lipid rafts from U251 cells with a descaler method and sucrose density gradient centrifugation. Afterwards, it was discovered via immunofluorescence that the lipid rafts contain a large amount of tropomyosin-related kinase A (TrkA) protein. Also, agarose powder in the lyophilised state was pretreated, before the lipid rafts were coupled to the agarose gel in a coupling buffer of alkaline pH. CNBr-Sepharose 4B affinity gel packing was characterised using UV spectrophotometric, immunofluorescence and scanning electron microscopic techniques, wherein and the results showed that the lipid rafts were successfully coupled to the agarose gels. Three compounds were used to verify the specific sorption of Sepharose 4B and CNBr-Sepharose 4B, which showed no specific sorption on the materials. Of note, the prepared Lipid [email protected] 4B agarose gels packed with TrkA-rich target proteins could be successfully validated for the active drug gefitinib with high affinity sorption efficiency and eluted with good recovery and reproducibility. This study broadens the range of affinity chromatography carrier materials and provides a reference for research in active drug screening.
研究领域:
生物化学
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药学
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生物技术
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分析化学
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产品关联
DOI
PubMed
高影响因子
CELL RESEARCH
·
2024
·
IF 28.1
Sun Ke,Li Sicong,Zheng Bowen,Zhu Yanlei,Wang Tongyue,Liang Mingfu,Yao Yue,Zhang Kairan,Zhang Jizhong,Li Hongyong,Han Dongyang,Zheng Jishen,Coventry Brian,Cao Longxing,Baker David,Liu Lei,Lu Peilong
Abiotic d -proteins that selectively bind to natural l -proteins have gained significant biotechnological interest. However, the underlying structural principles governing such heterochiral protein–protein interactions remain largely unknown. In this study, we present the de novo design of d -proteins consisting of 50–65 residues, aiming to target specific surface regions of l -proteins or l -peptides. Our designer d -protein binders exhibit nanomolar affinity toward an artificial l -peptide, as well as two naturally occurring proteins of therapeutic significance: the D5 domain of human tropomyosin receptor kinase A (TrkA) and human interleukin-6 (IL-6). Notably, these d -protein binders demonstrate high enantiomeric specificity and target specificity. In cell-based experiments, designer d -protein binders effectively inhibited the downstream signaling of TrkA and IL-6 with high potency. Moreover, these binders exhibited remarkable thermal stability and resistance to protease degradation. Crystal structure of the designed heterochiral d -protein– l -peptide complex, obtained at a resolution of 2.0 Å, closely resembled the design model, indicating that the computational method employed is highly accurate. Furthermore, the crystal structure provides valuable information regarding the interactions between helical l -peptides and d -proteins, particularly elucidating a novel mode of heterochiral helix–helix interactions. Leveraging the design of d -proteins specifically targeting l -peptides or l -proteins opens up avenues for systematic exploration of the mirror-image protein universe, paving the way for a diverse range of applications.
研究领域:
蛋白质工程
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生物技术
·
结构生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）